[Frontiers in Bioscience 7, d43-52, January 1, 2002]

IMMUNOTHERAPY OF CANCER USING HEAT SHOCK PROTEINS

Masoud H. Manjili 1, Xiang-Yang Wang 1, Juneui Park 1, John G. Facciponte 2 , Elizabeth A. Repasky 2 and John R. Subjeck 1

1 Department of Molecular and Cellular Biophysics, Roswell Park Cancer Institute, Buffalo, New York 14263, 2 Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York 14263

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Stress protein families and their immunological properties
3.1. Chaperoning properties
3.2. Peptide binding properties
3.3. Hsps interact with APCs
4. Immunogenicity of hsps
4.1. Tumor-derived hsp vaccines
4.2. Hsp-peptide based vaccines
4.3. Hsp-protein based vaccines
4.4. Hsp-based DNA vaccines
4.5. Hsp fusion protein vaccines
4.6. Cell-based vaccines
5. Improvement of hsp-based vaccination
5.1. Hsp-based vaccine combined with hyperthermia
5.2. Hsp-based vaccine combined with CTLA-4 blockade
6. Prospective
7. Acknowledgements
8. References

1. ABSTRACT

Tumor derived heat shock protein (hsp)-peptide complexes (particularly hsp70 and grp94/gp96) have been demonstrated to serve as effective vaccines, producing anti-tumor immune responses in animals and in man. This approach utilizes the peptide binding properties of stress proteins which are responsible for their functions as molecular chaperones in numerous cellular processes. The present review briefly introduces the reader to the basic stress protein families, i.e. heat shock and glucose regulated proteins, their regulation, compartmentalization and family members. It then introduces the reader to aspects of hsps/grp function and interactions with the host's immune system. An overview of the conventional uses of hsp/grp vaccines as autologous vaccines derived from cancers is presented. We then discuss other stress protein related vaccination approaches. This includes the use of recombinant antigens, both proteins and peptides, naturally complexed to hsp/grps; hsp/grp DNA vaccines, hsp/grp fusion proteins and cell based hsp/grp vaccines. The advantages and disadvantages of each vaccination approach are discussed. Lastly, means of further enhancing the already potent activity of stress protein vaccines are presented, specifically the use of hyperthermia or CTLA-4 blockade as adjuvants.